Premenopausal African-American women suffer disproportionately from a higher incidence of the basal-like triple-negative breast cancer compared to Caucasian-American patients. Currently, no effective molecular therapies exist for this highly aggressive cancer and, consequently, patient survival is poor. The majority of studies investigating differences in breast cancer between African- and Caucasian-American women examine tumor characteristics, however, the etiologic factors that lead to this disparity remain undefined. Our preliminary data implicate a role for HGF in breast cancer progression and in differences between African-American and Caucasian patients. To further understand the role of this pathway in cancer disparities we will address two Aims. Aim 1 will identify a gene expression signature for HGF via microarray analysis and use this signature to evaluate the expression of the HGF pathway in African-American vs. Caucasian patients and according to breast cancer subtype. Aim 2 will use primary cell lines from African- American and Caucasian patients to evaluate the effects of variation in HGF expression by fibroblasts on cancer cell phenotypes including proliferation and motility assays. Thus, our primary objective is to identify the mechanisms involved in the development of aggressive, metastatic breast cancer in premenopausal African-Americans, as a consequence of stromal effects at the site of the cancerous lesion. Our team has established research partnerships that provide access to resources including the Normal Breast Study: a unique epidemiologic study of normal tissue from ethnically diverse patients at UNC Hospitals. There are several important biological implications of this work. Tumor biology often takes advantage of existing normal tissue programs. By studying the cancer-adjacent tissue, in combination with tissue adjacent to tumor, we will learn which normal programs the tumor utilizes for progression, and these pathways may be targetable. The observation that the normal breast tissue of African-American women is enriched with proteins from programs distinct from Caucasian women, and that African-American women are predisposed to develop basal-like breast cancer strongly suggests a biological link between race and cancer subtype. The role of differentially regulated stromal-derived proteins in the tumor microenvironment will provide novel insights into the biological basis of racial disparities. The long-term goal of the Fleming-Troester collaboration is to understand tumor-microenvironment interactions and their influence on breast cancer disparities.